Omeprazole process and compositions thereof

ABSTRACT

The present invention describes an improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole whereby the sulfide precursor pyrmetazole is reacted subsurfacely with exactly one molar equivalent of meta-chloroperoxybenzoic acid in methylene chloride or toluene solution; residual organic solvent is removed from the aqueous layer by vacuum distillation; crude product is obtained by reactive crystallization with an alkyl formate and seeding; and pure product is isolated by recrystallization in methanol-water containing aqueous NaOH by subsurface addition of aqueous acetic acid to pH 9.0, seeding, filtration, washing, and drying. Compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of Ser. No. 09/169,231, filed Oct. 9,1998, which in turn is related to U.S. provisional application Ser. No.60/096,037 filed Aug. 11, 1998, the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention provides a novel improved process for thepreparation, isolation, and purification of the anti-ulcer agentomeprazole. Compositions of omeprazole containing no chromatographicallydetectable levels of residual non-alcoholic organic reaction solvent arealso disclosed.

BACKGROUND OF THE INVENTION

Omeprazole, the generic name for5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(denoted as Formula I below) is a well-described gastric proton-pumpinhibitor and is on the market as LOSEC® or PRILOSEC® for the treatmentof gastric and duodenal ulcers, gastritis, duodenitis, and refluxesophagitis (see Merck Index, 12th Ed., entry 6977, and references citedtherein). Omeprazole is commercially prepared via a multi-step sequence,the last step of which is oxidation of the sulfide intermediate,5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]methylthio]-1H-benzimidazole(denoted as Formula II below), known generically as pyrmetazole, whichis typically effected with a peroxy acid, such asmeta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S.Pat. Nos. 4,255,431 and 5,386,032), magnesium monoperoxyphthalate (MMPP)(U.S. Pat. No. 5,391,752), or peroxyacetic acid (WO 98/09962), in asuitable non-alcoholic organic reaction solvent. The preferred oxidizingagent is usually MCPBA, and suitable non-alcoholic organic reactionsolvents include aromatic hydrocarbon solvents, such as benzene andtoluene, and chlorinated aliphatic hydrocarbon solvents, such aschloroform and methylene chloride, in admixture with an alcoholicsolvent, such as methanol, ethanol, isopropanol, or 1-butanol. Thepreferred non-alcoholic organic reaction solvents are usually methylenechloride and toluene, and the preferred alcoholic solvent is ethanol.

Prior processes to omeprazole have numerous disadvantages that limitboth the yield and the purity of the final product.

A significant drawback of such prior methods is incomplete oxidativeconversion of pyrmetazole into omeprazole as well as non-chemoselectiveoxidation. Two aspects of chemoselectivity are important in theoxidation of pyrmetazole. First, pyrmetazole contains two tertiary aminogroups which can compete with the sulfide group for the oxidizing agent.Although these amino groups are less reactive than the desired sulfide,they can nevertheless undergo quantitative oxidation with MCPBA belowambient temperature. Second, the product omeprazole (a sulfoxide) canalso react with MCPBA to form a sulfone by-product. Non-chemoselectivityand over-oxidation, characteristic of the previous methods, arise fromineffective control over the amount of the oxidizing agent as well asthe manner in which the oxidizing agent is charged into the reactionvessel. Prior methods do not use accurately determined amounts of theoxidizing agent and do not provide for careful control of its additionto the reaction mixture. Non-chemoselective, over-, and under-oxidationall contribute to high impurities and loss of yield of the final desiredproduct.

Another disadvantage of prior procedures is the considerable loss ofproduct in the purification and isolation steps due to solubility ofomeprazole in the mother liquors and solvent washes.

A further drawback concerns diminished product quality resulting fromocclusion of residual solvents and reaction by-products during thecrystallization steps. It is desirable to eliminate residual levels oforganic reaction solvent and recrystallization solvent impurities in thefinal crystalline product for toxicity/safety reasons.

It is therefore an object of the present invention to provide animproved process for the preparation, purification, and isolation ofomeprazole that overcomes the yield and product purity limitations ofprior methods.

It is also an object of the invention to provide compositions ofomeprazole having lower levels of residual non-alcoholic organicreaction solvent after the initial crude reactive crystallization step.

It is a further object of the present invention to provide finalcompositions of omeprazole that contain no residual non-alcoholicorganic reaction solvent within the limits of chromatographic detectionand less than 20 p.p.m. of residual crystallization solvent.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation,purification, and isolation of omeprazole of the Formula I.

The last chemical transformation in the preparation of omeprazole is theoxidative conversion of the sulfide intermediate pyrmetazole of theFormula II into its sulfoxide derivative omeprazole of the Formula I.##STR1##

In one embodiment of the improved process, the oxidizing agent ismeta-chloroperoxybenzoic acid (MCPBA), and the non-alcoholic organicreaction solvent is methylene chloride or toluene in admixture with analcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol,in particular, ethanol. In this embodiment, the completeness andchemoselectivity of the oxidation have been optimized by careful controlof the amount of MCPBA charged to the reaction vessel. The use of onemolar equivalent of MCPBA relative to the number of moles of pyrmetazoleprevents non-chemoselective, over-, and under-oxidation resulting infewer impurities and higher yields. In another embodiment of the presentinvention, the concentration of MCPBA in the charging solution iscalculated using a novel analytical method based upon MCPBA oxidation of3-methylisoquinoline to its N-oxide derivative and subsequent HPLCquantitation. Without this assay there exists no practical way to avoideither over-oxidation or incomplete conversion of pyrmetazole intoomeprazole.

In a further embodiment of the present invention, control over localizedover-oxidation is achieved by subsurface addition of MCPBA, providingfor entry of the oxidizing solution into the reaction vessel at the tipof the agitator blades, with simultaneous control of the reactiontemperature. Incorporation of these novel features into the processensures complete conversion of pyrmetazole into omeprazole with noformation of sulfone by-products.

In another embodiment of the present invention, the isolation of thecrude product has been improved by vacuum distillation of the crudeaqueous phase after extraction of the reaction mixture prior tocrystallization to remove most of the entrained methylene chloride ortoluene from the oxidation step. The alcoholic solvent, in particularethanol, concentration is re-adjusted in order to promote good crystalgrowth during the crude crystallization step. The crystallization stepinvolves a two-stage neutralization with a C₁₋₃ alkyl formate,preferably methyl formate, which is added subsurfacely through a diptubelocated near and directed perpendicular to the impeller tip. This modeof addition of the methyl formate ensures rapid dispersion of theneutralizing agent, which promotes crystal growth over spontaneousnucleation. In so doing, occlusion of mother liquors in the crystals isminimized. Lowering the concentration of ammonia, relative to that usedin prior procedures, in the ammonia-water wash, necessary to removecolor impurities in the crude product, provides for further improvementin the yield of omeprazole.

A further embodiment of the present invention concerns the finalpurification step. A methanol-water mixture is used for thecrystallization step which is initiated by subsurface addition ofaqueous acetic acid and subsequent seeding with omeprazole. The samemethanol-water mixture is employed as a displacement wash to removemother liquors and dissolved impurities while suppressing solubilitylosses. In this fashion, significant yield improvements are obtainedwith no adverse impact on product quality.

Crystalline omeprazole is thus obtained with significant improvement inyield and purity. The isolated material contains no chromatographicallydetectable levels of residual non-alcoholic organic reaction solvent andless than 20 p.p.m. of residual methanol as the crystallization solvent.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

The instant invention relates to an improved process for thepreparation, purification, and isolation of the proton-pump inhibitoromeprazole and to novel compositions thereof. Omeprazole, having formulaI, is prepared by reacting a solution of pyrmetazole, having Formula II,cooled to about -5 to +5° C. and buffered to a pH of about 5 to 6,##STR2## with one molar equivalent of an oxidizing agent, relative tothe number of moles of pyrmetazole, dissolved in a non-alcoholic organicreaction solvent in admixture with an alcoholic solvent. The alcoholicsolvent is selected from methanol, ethanol, isopropanol, and 1-butanol.

In one embodiment of the instant improved process, the buffered solutioncomprises potassium bicarbonate, the oxidizing agent ismeta-chloroperoxybenzoic acid, and the non-alcoholic organic reactionsolvent is methylene chloride or toluene, either in admixture withethanol. The reaction is carried out such that both completeness andchemoselectivity of the oxidation are optimized. To force the reactionto proceed in a near quantitative fashion, it is necessary that anyexcess of the oxidizing agent, MCPBA, be minimized. Hence, the solutioncontaining the oxidizing agent is accurately assayed so that an exactamount of reagent will be charged to the reaction vessel. In priormethods, the amount of MCPBA added was based on the commercialsupplier's assay number. Since MCPBA solid contains about 15-25% waterfor safety reasons, the solid is not homogeneous. Therefore, themanufacturer can provide only the average assay results of MCPBA. IfMCPBA from different containers and different suppliers is used, aninaccurate charge of MCPBA will result. A novel analytical method hastherefore been developed to quantify MCPBA in the charging solution inorder to deliver an accurate amount of the oxidizing agent. According tothe assay, an excess amount of 3-methylisoquinoline (III) is reactedwith CPBA in toluene/ethanol solution to form 3-methylisoquinolineN-oxide (IV), according to the equation: ##STR3## The reaction is fastand quantitative. The remaining tertiary amine in the reaction mixtureis quantitated by reverse-phase high-performance liquid chromatography(RP-HPLC). The amount of the amine consumed during the reaction is usedto calculate the concentration of the MCPBA solution.

It is also important that no excess oxidizing agent accumulate duringaddition of the reagent. This is best accomplished by subsurfaceaddition of MCPBA, such that the solution enters the batch through adiptube located near and directed perpendicular to the agitator blades.This mode of addition provides for immediate dispersion of the oxidant,thus limiting localized over-oxidation.

Chemoselectivity and extent of oxidation are also enhanced bycontrolling the reaction temperature without crystallization of theoxidizing agent. The optimum temperature range is about 0-5° C. for thesolution of the oxidizing agent and about -5 to +5° C. for the reactionmixture throughout the addition process. Higher temperatures of eitherthe MCPBA solution or the reaction mixture will result in some sulfoneformation. Likewise, much lower temperatures temporarily suppress theoxidation reaction, which results in a localized accumulation of theoxidizing a gent that can lead to over-oxidation products.

After addition of the solution containing the oxidizing gent, aqueousbase, for example 50% NaOH or KOH, is added, the solution allowed to agefor about 0.5-1.0 hours at 0-5° C., and the aqueous phase separated fromthe organic phase. To minimize residual levels of the non-alcoholicorganic reaction solvent, in particular toluene or methylene chloride,in the crude product, which translates into higher levels of volatilenon-alcoholic organic reaction solvent in the pure product, it isimportant to remove as much entrained toluene or methylene chloride aspossible from the crude aqueous phase. The source of residual toluene ormethylene chloride is an emulsion that forms when the crude batch isextracted from toluene or methylene chloride with aqueous base. Removalof residual solvent may be accomplished by vacuum distillation of theaqueous phase at a pressure of about 25-70 mm Hg and temperature ofabout 15-35° C. for about 1-4 hours. In further exemplification, thedistillation is carried out at about 50 mm Hg and about 15° C. for 2hours. The vacuum distillation procedure reduces the pre-crystallizationlevels of toluene or methylene chloride to less than 400 p.p.m. Otheroptions to break up the emulsion and effect better phase separation areless effective; these include filtration of the crude aqueous phasethrough a bed of Celite™, increasing the settling time, and addition ofa strong electrolyte.

Since the distillation process also results in removal of the alcohol,in particular ethanol, its concentration must be re-adjusted toapproximately 15%, in order to facilitate crystal growth during thecrude crystallization process. A lower level of the alcoholic solvent,in particular ethanol, produces finer crystals which are more likely todissolve during subsequent washes thereby diminishing yields of thecrude product.

At this point, the reactive crystallization of omeprazole is initiatedand maintained under controlled conditions. Approximately 40% of a C₁₋₃-alkyl formate charge, preferably methyl formate, is added over thefirst 30 minutes to bring the batch from a pH of about 13.5 to nearsupersaturation at a pH of about 10.6 to 10.8. The methyl formateaddition is accomplished through a diptube which is narrowed at one endto create a fine stream and which is located near and perpendicular tothe impeller tip. This technique ensures rapid dispersion of the methylformate so that occlusion of impurities is minimized. When a pH of about10.6-10.8 is attained, the methyl formate addition is discontinued, andthe batch is aged for ten to twenty minutes to allow the temperature tocool to approximately 20° C. prior to seeding. It is important to seedbetween pH 10.6 and 10.8. Below 10.6 spontaneous nucleation will occurwith little crystal growth, if a sufficient seed bed is not present.Seeding is effected with pure, milled omeprazole (100% by HPLC), and therest of the methyl formate is added subsurfacely over 6-8 hours toadjust the pH to about 9.0-9.3. This crystallization procedure improvesboth the yield and purity of the product. Without being held to aspecific mechanism, it is believed that the purity enhancement is mainlydue to preventing occlusion of mother liquors by promoting crystalgrowth over nucleation. Crude omeprazole at this stage contains lessthan 100 p.p.m. of residual toluene or methylene chloride, as determinedby gas-liquid chromatographic analysis.

The crude crystallized product is then filtered, washed with 0.01-1.0%,preferably 0.1%, ammonia-water, and then methanol.

The crude wet omeprazole is then purified by dissolving it in 2:1-0.5-1(v/v) methanol-water solution containing aqueous base, preferably 50%NaOH or KOH, at 20° C., cooling the basic solution to about 0-5° C.,reducing the pH from >11.0 to approximately 10.5 by subsurface additionthrough a narrowed end diptube (configuration of apparatus same as incrude isolation step) of aqueous acetic acid, preferably 25% aqueousacetic acid, over a 30-minute period, while maintaining the temperatureat 0-5° C. At this point the batch is seeded with pure omeprazole (100%by HPLC), and the subsurface addition of 25% aqueous acetic acid iscontinued over a 2-4 hour period until a pH of about 9.0 is attained.The batch is then aged for 0.5-1.0, preferably 0.5, hours. Following theaging period, the product is filtered, washed with the samemethanol-water mixture to displace the mother liquors containing theimpurities, and finally with cold methanol. Pure omeprazole is obtainedafter vacuum drying with a nitrogen purge at 30-50 mm Hg and 30-35° C.

The optimal methanol-water ratio in this final purification step is 1:1.Previous methods used a higher methanol to water ratio. Lowering theproportion of methanol in the solvent mixture used in the displacementwash minimizes solubility losses and provides the purification demands,thereby improving the yield of the final product without compromisingproduct quality.

Crystalline omeprazole obtained using the improved process of theinstant invention has an HPLC purity of 100% with no detectable levelsof entrained residual toluene or methylene chloride from the crude stepas measured by gas-liquid chromatography, the detection limit being 3p.p.m. Prior methods have afforded omeprazole containing 30-100 p.p.m.of residual non-alcoholic organic reaction solvent, namely toluene ormethylene chloride. The pure product contains less than 20 p.p.m. ofresidual methanol as the crystallization solvent.

For the preparation of pharmaceutical compositions in the form of dosageunits for oral administration, omeprazole prepared according to theprocess of the present invention may be mixed with a solid, pulverulentcarrier, such as lactose, saccharose, sorbitol, mannitol, starch,amylopectin, cellulose derivatives or gelatin, as well as anantifriction agent such as magnesium stearate, calcium stearate, andpolyethyleneglycol waxes. The mixture is then pressed into tablets. Ifcoated tablets are desired, the above-prepared core may be coated with aconcentrated solution of sugar, which may contain gum arabic, gelatin,talc, titanium dioxide, or with a lacquer dissolved in volatile organicsolvent or mixture of solvents. To this coating various dyes may beadded in order to distinguish among tablets with different amounts ofactive compound present.

Soft gelatin capsules may be prepared which contain a mixture of pureomeprazole prepared according to the process of the present inventionand vegetable oil. Hard gelatin capsules may contain granules of theactive compound in combination with a solid, pulverulent carrier, suchas lactose, saccharose, sorbitol, mannitol, potato starch, corn starch,amylopectin, cellulose derivatives, or gelatin.

Pharmaceutical tablets for oral use are prepared in the followingmanner. The solid substances are ground or sieved to a certain particlesize, and the binding agent is homogenized and suspended in a suitablesolvent. The solid omeprazole prepared according to the process of thepresent invention and auxiliary agents are mixed with the binding agentsolution. The resulting mixture is moistened to form a uniformsuspension having the consistency of wet snow. The moistening causes theparticles to aggregate slightly, and the resulting mass is pressedthrough a stainless steel sieve having a mesh size of about 1millimeter. The layers of the mixture are dried in carefully controlleddrying cabinets for approximately ten hours to obtain the desiredparticle size and consistency. The granules of the dried mixture aresieved to remove any powder. To this mixture, disintegrating,antifriction, and antiadhesive agents are added. Finally, the mixture ispressed into tablets using a machine with the appropriate punches anddies to obtain the desired tablet size. The pressure applied affects thesize of the tablet, its strength and ability to dissolve in water. Thecompression pressure used should be in the range of 0.5 to 5 tons. Thetablets, especially those which are rough or bitter, may be coated witha layer of sugar or some other palatable substance. They are thenpackaged by machines having electronic counting devices.

The following examples illustrate the process of the present inventionand are not intended to limit the scope of the invention set forth inthe claims appended thereto.

EXAMPLE 1 HPLC Assay of MCPBA Charging Solution

Step A. HPLC Operating Parameters

High-performance liquid chromatography was performed using a WatersμBondapak C-18 column (4.6×300 mm, 10 μm particle size) with thefollowing additional parameters:

Mobile phase: A=acetonitrile; B=0.1% H₃ PO₄

Mode: isocratic 25%A/75%B at a flow rate of 1.0 mL/min

Injection size: 10 μL

Detector wavelength: 254 nm

Run time: 32 min.

Method of quantitation: Area by electronic integration

Approximate retention times: 3-methylisoquinoline: 3.5 mins.

3-methylisoquinoline N-oxide: 5.7 mins.

MCPBA: 11.4 mins.

Toluene: 25.1 mins.

    ______________________________________                                        Step B.  Reagents                                                             ______________________________________                                               Acetonitrile (MeCN):                                                                       HPLC Grade                                                       Water:       HPLC Grade                                                       Phosphoric Acid:                                                                           HPLC Grade                                                       3-Methylisoquinoline:                                                                      98%                                                              Sample Diluent:                                                                            50/50 (MeCN/0.1% H.sub.3 PO.sub.4)                        ______________________________________                                    

Step C. Preparation of 3-Methylisoguinoline Standard

20±5 mg of 3-methylisoquinoline (98%) was transferred into a 10 mLvolumetric flask and dissolved in 1.0 mL of MeCN. 1.0 mL of MCPBA afterwarming to room temperature was carefully pipetted into the flask, andthe sides of the flask were washed with 1.0 mL of MeCN. The flask wasthen wrapped with parafilm and sonicated for 5 minutes. After cooling,the sides of the flask were washed with 1.0 mL of MeCN and the flasksonicated for an additional minute. The mixture was carefully diluted tothe mark with acetonitrile. 1.0 mL of this solution was transferred bypipet to a 25-mL volumetric flask and diluted to the mark with thesample diluent from Step B.

Step D. Procedures

The HPLC system was equilibrated for at least 10 minutes at the mobilephase condition given in Step A. The standard preparation from Step Cwas injected twice, and the average area response for the3-methylisoquinoline peaks should agree within ±1% of their average. Thesample preparation was injected once.

Step E. Calculations

The concentration (mg/mL) of the MCPBA solution was calculated using thefollowing equation: ##EQU1## where: A=area response of the3-methylisoquinoline for the Sample Solution

B=weight (mg) of the 3-methylisoquinoline in the Sample Preparation

As=average area response of the 3-methylisoquinoline for the StandardSolution

Cs=concentration of the 3-methylisoquinoline Standard Preparation

172.57=formula weight for 3-methylisoquinoline

143.19=formula weight for MCPBA

As an illustration of the assay, an MCPBA sample from Spectrum (Lot#LF0102, 72.7% MCPBA) was assayed, and a value of 72.8% (wt. %) for MCPBAwas obtained.

EXAMPLE 2 Preparation of Omeprazole with Methylene Chloride as Solvent

A solution of potassium bicarbonate (14.0 g, 0.140 mol, 1.2 equivalents)in deionized water (115 mL) was added to a solution of pyrmetazole(0.114 mol) in methylene chloride (170 mL) in a one-liter, three-neckedround-bottom flask, and the mixture was cooled to 0° C. A solution ofmeta-chloroperoxybenzoic acid (MCPBA) (28 g, 0.114 mol, 1.0 equivalent)in methylene chloride (51 mL) and ethanol (13.3 mL) was prepared andassayed by the 3-methylisoquinoline/HPLC procedure described in Example1 to ensure that exactly one molar equivalent of MCPBA is used. Thesolution is then cooled between 0-5° C. and added, subsurfacely directedat the tip of the impeller, to the rapidly agitated solution ofpyrmetazole over a 2-hour period. The oxidation conversion was 99.8%with no over-oxidation to sulfone or N-oxides, as determined by HPLCanalysis. Cold deionized water (115 mL, 5° C.) and 50% NaOH (15 mL) werethen added to the reaction mixture. The solution was allowed to stand at0-5° C. for thirty minutes and the phases separated. The methylenechloride layer was discarded and the aqueous layer concentrated undervacuum (50 mm Hg) for 2 hours at 15° C. to remove the bulk of theresidual methylene chloride. The ethanol level was then re-adjusted to15% v/v. At this point the residual methylene chloride level was lessthan 200 p.p.m., as determined by gas-liquid chromatographic analysis.

The crude product was then isolated by reactive crystallization bysubsurface addition of methyl formate. Approximately 40% of the methylformate charge (approximately 6 mL) was added during the first thirtyminutes to adjust the pH from about 13.5 to 10.8. The mixture wasallowed to stand for about twenty minutes to allow the internaltemperature to cool back down to approximately 20° C. The mixture wasseeded with pure omeprazole (0.5 g), and the remainder of the methylformate (approximately 9 mL) was added subsurfacely over a 7-hour periodto a pH of 9.0. The crude product was filtered, washed with 0.1%ammonia-water (50 mL) followed by methanol (40 mL).

The crude product was dissolved in 1:1 methanol-water (270 mL) and 50%NaOH (4 mL) in a 500-mL, three-necked, round-bottomed flask at 20° C.The solution was then cooled to 0-5° C. and the pH adjusted from >11.0to approximately 10.5 by subsurface addition of 25% acetic acid over a30-minute period, maintaining the temperature at 5° C. The batch wasseeded with pure omeprazole (0.5 g), and the subsurface addition of 25%acetic acid was continued over a 4-hour period until pH 9.0 wasachieved. After thirty minutes, the resulting solid was filtered, washedwith 1:1 methanol-water (30 mL), and finally with cold (5° C.) methanol(30 mL). Pure omeprazole (100% as determined by HPLC analysis) wasobtained after vacuum drying (50 mm Hg, 30-35° C.). The overall yieldwas 92.7%. The residual methanol level was 10 ppm, as determined bygas-liquid chromatography, with no detectable levels of methylenechloride (detection limit of 3 p.p.m.).

EXAMPLE 3 Preparation of Omeprazole with Toluene as Solvent

A solution of potassium bicarbonate (14.0 g, 0.140 mol, 1.2 equivalents)in deionized water (115 mL) was added to a solution of pyrmetazole(0.114 mol) in toluene (310 mL) in a one-liter, three-neckedround-bottom flask, and the mixture was cooled to 0° C. Following thebicarbonate addition, a solution of meta-chloroperoxybenzoic acid (0.114mol, 1 equivalent) in toluene (53 mL) and ethanol (20 mL) was assayedand charged to the pyrmetazole solution as in Example 2. The oxidationconversion was 99.8% with no over-oxidation to sulfone or N-oxides. Colddeionized water (145 mL, 5° C.) and 50% NaOH (12 mL) were then added tothe reaction mixture. The solution was allowed to stand at 0-5° C. forthirty minutes and the phases separated. The toluene layer was discardedand the aqueous layer concentrated under vacuum (50 mm Hg) for 2 hoursat 15° C. to remove the bulk of the residual toluene. The ethanol levelwas then adjusted to 15% v/v. At this point the residual toluene levelwas less than 400 p.p.m., as determined by gas-liquid chromatographicanalysis.

The crude product was then isolated by reactive crystallization bysubsurface addition of methyl formate as in Example 2. It was filtered,washed with 0.1% ammonia-water (50 mL) followed by methanol (40 mL). Thewet crude product was then processed to pure omeprazole as in Example 2.The overall yield was 93.8% with an HPLC purity of 100%. The residualmethanol level was 10 ppm, as determined by gas-liquid chromatography,with no detectable levels of toluene (detection limit 3 p.p.m).

EXAMPLE 4

A pharmaceutical composition containing omeprazole prepared according tothe process of the present invention as the active ingredient isillustrated in the following formulation.

Capsules containing 30 mg of omeprazole of the present invention wereprepared from the following ingredients:

    ______________________________________                                        Compound of Example 2 or 3                                                                            300    grams                                          Lactose                 700    grams                                          Microcrystalline cellulose                                                                            40     grams                                          Hydroxypropyl cellulose, low substituted                                                              62     grams                                          Disodium hydrogenphosphate                                                                            2      grams                                          Purified water          q.s.                                                  ______________________________________                                    

The omeprazole of Example 2 or 3 was mixed with the dry ingredients andgranulated with a solution of disodium hydrogenphosphate. The wet masswas forced through an extruder and sphreronized and dried in a fluidizedbed dryer.

500 Grams of the pellets were coated with a solution of hydroxypropylmethylcellulose (30 grams) in water (750 mL) using a fluidized bedcoater. After drying, the pellets were coated with a second coating asfollows:

    ______________________________________                                        Coating solution:                                                             ______________________________________                                        Hydroxypropyl methylcellulose phthalate                                                               70 grams                                              Cetyl alcohol           4 grams                                               Acetone                200 grams                                              Ethanol                600 grams                                              ______________________________________                                    

The final coated pellets were filled into capsules.

What is claimed is:
 1. A composition comprising5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(omeprazole) having less than three parts per million of residualaromatic hydrocarbon solvent and less than 20 p.p.m. of residualmethanol relative to omeprazole.
 2. A composition comprising5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(omeprazole) having less than three parts per million of residualchlorinated aliphatic hydrocarbon solvent and less than 20 p.p.m. ofresidual methanol relative to omeprazole.
 3. The composition accordingto claim 1 wherein the aromatic hydrocarbon solvent is toluene.
 4. Thecomposition according to claim 2 wherein the chlorinated aliphatichydrocarbon solvent is methylene chloride.
 5. A pharmaceuticalcomposition comprising5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(omeprazole) having less than three parts per million of residualaromatic hydrocarbon solvent and less than 20 p.p.m. of residualmethanol relative to omeprazole, and a pharmaceutically acceptableexcipient.
 6. A pharmaceutical composition comprising5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleomeprazole) having less than three parts per million of residualchlorinated aliphatic hydrocarbon solvent and less than 20 p.p.m. ofresidual methanol relative to omeprazole, and a pharmaceuticallyacceptable excipient.
 7. The pharmaceutical composition according toclaim 5 wherein the aromatic hydrocarbon solvent is toluene.
 8. Thepharmaceutical composition according to claim 6 wherein the chlorinatedaliphatic hydrocarbon solvent is methylene chloride.